Major TCR repertoire perturbation by immunodominant HLA-B*44:03 - restricted CMV - specific T cells

Attaf, Meriem, Malik, Amna, Severinsen, Mai C., Roider, Julia, Ogongo, Paul, Buus, Søren, Ndung'u, Thumbi, Leslie, Alasdair, Kløverpris, Henrik N., Matthews, Philippa C., Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135 and Goulder, Philip 2018. Major TCR repertoire perturbation by immunodominant HLA-B*44:03 - restricted CMV - specific T cells. Frontiers in Immunology , 2539. 10.3389/fimmu.2018.02539

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Abstract

Lack of disease during chronic human cytomegalovirus (CMV) infection depends on the maintenance of a high-frequency CMV-specific T cell response. The composition of the T cell receptor (TCR) repertoire underlying this response remains poorly characterised, especially within African populations in which CMV is endemic from infancy. Here we focus on the immunodominant CD8+ T cell response to the immediate-early 2 (IE-2)-derived epitope NEGVKAAW (NW8) restricted by HLA-B*44:03, a highly prevalent response in African populations, which in some subjects represents >10% of the circulating CD8+ T cells. Using pMHC multimer staining and sorting of NW8-specific T cells, the TCR repertoire raised against NW8 was characterised here using high-throughput sequencing in 20 HLA-B*44:03 subjects. We found that the CD8+ T cell repertoire raised in response to NW8 was highly skewed and featured preferential use of a restricted set of V and J gene segments. Furthermore, as often seen in immunity against ancient viruses like CMV and Epstein-Barr virus (EBV), the response was strongly dominated by identical TCR sequences shared by multiple individuals, or “public” TCRs. Finally, we describe a pair “superdominant” TCR clonotypes, which were germline or nearly germline-encoded and produced at remarkably high frequencies in certain individuals, with a single CMV-specific clonotype representing up to 17% of all CD8+ T cells. Given the magnitude of the NW8 response, we propose that this major skewing of CMV-specific immunity leads to massive perturbations in the overall TCR repertoire in HLA-B*44:03 individuals

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Frontiers Media
ISSN:	1664-3224
Date of First Compliant Deposit:	18 December 2018
Date of Acceptance:	15 October 2018
Last Modified:	06 May 2023 10:42
URI:	https://orca.cardiff.ac.uk/id/eprint/117747

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